The objectives of this research are the elucidation of relationships between the three-dimensional structure and the function of biological molecules. At present the major project is the X-ray crystallographic determination of the structure of aspartate transcarbamylase (ATCase), molecular weight 310,000, a multisubunit enzyme having six regulatory and six catalytic subunits per molecule. ATCase is inhibited by CTP and activated by ATP and is thought to be involved in the regulation of the pyrimidine biosynthetic pathway. This modulation of enzymatic activity is the result of conformational transitions induced by the binding of substrates and allosteric effectors. The structure of ATCase in different conformational states should reveal the molecular basis of these allosteric transitions. A 5.5 A electron density map of the native enzyme has been computed and work is progressing on the high resolution structure. In addition several ATCase complexes are under investigation. Chemical studies are in progress which support and complement the structural investigation. These include chemical modifications, spectrophotometric and kinetic studies. Information concerning the dynamic aspects of enzyme mechanism and regulation will be correlated with the structures of the static conformational states observed crystallographically. In addition theoretical studies of the electronic structure and activity of enzymes are underway, using approximate molecular orbital theory. This method should reveal the nature of the binding forces and changes in the electronic structure of the substrate during catalysis.